Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation

James D. Fisher, Stephen C. Balmert, Wensheng Zhang, Riccardo Schweizer, Jonas T. Schnider, Chiaki Komatsu, Liwei Dong, Vasil E. Erbas, Jignesh V. Unadkat, Ali Mübin Aral, Abhinav P. Acharya, Yalcin Kulahci, Heth R. Turnquist, Angus W. Thomson, Mario G. Solari, Vijay S. Gorantla, Steven R. Little

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

For individuals who sustain devastating composite tissue loss, vascularized composite allotransplantation (VCA; e.g., hand and face transplantation) has the potential to restore appearance and function of the damaged tissues. As with solid organ transplantation, however, rejection must be controlled by multidrug systemic immunosuppression with substantial side effects. As an alternative therapeutic approach inspired by natural mechanisms the body uses to control inflammation, we developed a system to enrich regulatory T cells (Tregs) in an allograft. Microparticles were engineered to sustainably release TGF-β1, IL-2, and rapamycin, to induce Treg differentiation from naïve T cells. In a rat hindlimb VCA model, local administration of this Treg-inducing system, referred to as TRI-MP, prolonged allograft survival indefinitely without long-term systemic immunosuppression. TRI-MP treatment reduced expression of inflammatory mediators and enhanced expression of Treg-associated cytokines in allograft tissue. TRI-MP also enriched Treg and reduced inflammatory Th1 populations in allograft draining lymph nodes. This local immunotherapy imparted systemic donor-specific tolerance in otherwise immunocompetent rats, as evidenced by acceptance of secondary skin grafts from the hindlimb donor strain and rejection of skin grafts from a third-party donor strain. Ultimately, this therapeutic approach may reduce, or even eliminate, the need for systemic immunosuppression in VCA or solid organ transplantation.

Original languageEnglish (US)
Pages (from-to)25784-25789
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number51
DOIs
StatePublished - Dec 17 2019
Externally publishedYes

Keywords

  • biomaterials
  • controlled release
  • drug delivery
  • regulatory T cells
  • transplantation

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation'. Together they form a unique fingerprint.

Cite this